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PKCβ positively regulates RANKL-induced osteoclastogenesis by inactivating GSK-3β.

Shin J, Jang H, Lin J, Lee SY - Mol. Cells (2014)

Bottom Line: However, the role of PKC in receptor activator of NF-κB ligand (RANKL) signaling has remained elusive.The administration of PKC inhibitor to the RANKL-injected mouse calvaria efficiently protected RANKL-induced bone destruction.Our results also provide a further rationale for PKCβ's therapeutic targeting to treat inflammation-related bone diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science and the Research Center for Cellular Home-ostasis, Ewha Womans University, Seoul 120-750, Korea.

ABSTRACT
Protein kinase C (PKC) family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. However, the role of PKC in receptor activator of NF-κB ligand (RANKL) signaling has remained elusive. We now demonstrate that PKCβ acts as a positive regulator which inactivates glycogen synthase kinase-3β (GSK-3β) and promotes NFATc1 induction during RANKL-induced osteoclastogenesis. Among PKCs, PKCβ expression is increased by RANKL. Pharmacological inhibition of PKCβ decreased the formation of osteoclasts which was caused by the inhibition of NFATc1 induction. Importantly, the phosphorylation of GSK-3β was decreased by PKCβ inhibition. Likewise, down-regulation of PKCβ by RNA interference suppressed osteoclast differentiation, NFATc1 induction, and GSK-3β phosphorylation. The administration of PKC inhibitor to the RANKL-injected mouse calvaria efficiently protected RANKL-induced bone destruction. Thus, the PKCβ pathway, leading to GSK-3β inactivation and NFATc1 induction, has a key role in the differentiation of osteoclasts. Our results also provide a further rationale for PKCβ's therapeutic targeting to treat inflammation-related bone diseases.

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Related in: MedlinePlus

Effects of Gö6976 on RANKL-induced bone loss in mice. RANKL administered locally on calvarial bone of 6-week-old male mice induces bone destruction. Injecting Gö6976 inhibited RANKL-induced bone resorption by osteoclasts which increased in number in the RANKL-administered group compared to that in the control group (PBS). (A) Histology of the calvarial bone injected with PBS, RANKL, or two different doses of Gö6976 (TRAP and hematoxylin staining). Scale bar, 50 μm. (B) Eroded surface and the number of osteoclasts on calvarial bone section were measured and analyzed using Osteomeasure XP. Data represent means ± S.D. n = 5. *P < 0.05, **P < 0.01.
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f4-molcell-37-10-747: Effects of Gö6976 on RANKL-induced bone loss in mice. RANKL administered locally on calvarial bone of 6-week-old male mice induces bone destruction. Injecting Gö6976 inhibited RANKL-induced bone resorption by osteoclasts which increased in number in the RANKL-administered group compared to that in the control group (PBS). (A) Histology of the calvarial bone injected with PBS, RANKL, or two different doses of Gö6976 (TRAP and hematoxylin staining). Scale bar, 50 μm. (B) Eroded surface and the number of osteoclasts on calvarial bone section were measured and analyzed using Osteomeasure XP. Data represent means ± S.D. n = 5. *P < 0.05, **P < 0.01.

Mentions: To investigate the effects of pharmacologically inhibiting PKCβ in the RANKL-induced bone loss model, we injected RANKL or PBS together with Gö6976 subperiosteally into the midline calvaria of 6-week-old mice. The extent of bone erosion was notably reduced in Gö6976-treated mice, and the formation of TRAP+ MNCs was greatly suppressed in a dose-dependent manner (Figs. 4A and 4B), suggesting that Gö6976 inhibits RANKL-induced bone loss in vivo. Thus, these results suggest that inhibiting PKCβ can provide a new therapeutic strategy targeting osteoclasts for treatment of bone diseases.


PKCβ positively regulates RANKL-induced osteoclastogenesis by inactivating GSK-3β.

Shin J, Jang H, Lin J, Lee SY - Mol. Cells (2014)

Effects of Gö6976 on RANKL-induced bone loss in mice. RANKL administered locally on calvarial bone of 6-week-old male mice induces bone destruction. Injecting Gö6976 inhibited RANKL-induced bone resorption by osteoclasts which increased in number in the RANKL-administered group compared to that in the control group (PBS). (A) Histology of the calvarial bone injected with PBS, RANKL, or two different doses of Gö6976 (TRAP and hematoxylin staining). Scale bar, 50 μm. (B) Eroded surface and the number of osteoclasts on calvarial bone section were measured and analyzed using Osteomeasure XP. Data represent means ± S.D. n = 5. *P < 0.05, **P < 0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4213766&req=5

f4-molcell-37-10-747: Effects of Gö6976 on RANKL-induced bone loss in mice. RANKL administered locally on calvarial bone of 6-week-old male mice induces bone destruction. Injecting Gö6976 inhibited RANKL-induced bone resorption by osteoclasts which increased in number in the RANKL-administered group compared to that in the control group (PBS). (A) Histology of the calvarial bone injected with PBS, RANKL, or two different doses of Gö6976 (TRAP and hematoxylin staining). Scale bar, 50 μm. (B) Eroded surface and the number of osteoclasts on calvarial bone section were measured and analyzed using Osteomeasure XP. Data represent means ± S.D. n = 5. *P < 0.05, **P < 0.01.
Mentions: To investigate the effects of pharmacologically inhibiting PKCβ in the RANKL-induced bone loss model, we injected RANKL or PBS together with Gö6976 subperiosteally into the midline calvaria of 6-week-old mice. The extent of bone erosion was notably reduced in Gö6976-treated mice, and the formation of TRAP+ MNCs was greatly suppressed in a dose-dependent manner (Figs. 4A and 4B), suggesting that Gö6976 inhibits RANKL-induced bone loss in vivo. Thus, these results suggest that inhibiting PKCβ can provide a new therapeutic strategy targeting osteoclasts for treatment of bone diseases.

Bottom Line: However, the role of PKC in receptor activator of NF-κB ligand (RANKL) signaling has remained elusive.The administration of PKC inhibitor to the RANKL-injected mouse calvaria efficiently protected RANKL-induced bone destruction.Our results also provide a further rationale for PKCβ's therapeutic targeting to treat inflammation-related bone diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science and the Research Center for Cellular Home-ostasis, Ewha Womans University, Seoul 120-750, Korea.

ABSTRACT
Protein kinase C (PKC) family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. However, the role of PKC in receptor activator of NF-κB ligand (RANKL) signaling has remained elusive. We now demonstrate that PKCβ acts as a positive regulator which inactivates glycogen synthase kinase-3β (GSK-3β) and promotes NFATc1 induction during RANKL-induced osteoclastogenesis. Among PKCs, PKCβ expression is increased by RANKL. Pharmacological inhibition of PKCβ decreased the formation of osteoclasts which was caused by the inhibition of NFATc1 induction. Importantly, the phosphorylation of GSK-3β was decreased by PKCβ inhibition. Likewise, down-regulation of PKCβ by RNA interference suppressed osteoclast differentiation, NFATc1 induction, and GSK-3β phosphorylation. The administration of PKC inhibitor to the RANKL-injected mouse calvaria efficiently protected RANKL-induced bone destruction. Thus, the PKCβ pathway, leading to GSK-3β inactivation and NFATc1 induction, has a key role in the differentiation of osteoclasts. Our results also provide a further rationale for PKCβ's therapeutic targeting to treat inflammation-related bone diseases.

Show MeSH
Related in: MedlinePlus